Article with foamed surface, implant and method of producing the same

ABSTRACT

A method of producing an article with a foamed surface which includes: a step 1 of forming small pores in a surface of a base made of a plastic to produce a base with small pores; a step 2 of immersing the base with small pores, obtained in step 1, in a solution including a foaming agent to prepare a foaming agent-including base; a step 3 of immersing the foaming agent-including base, obtained in step 2, in a foaming solution that makes the plastic swell and the foaming agent foam to prepare a foamed base; and a step 4 of immersing the foamed base, obtained in step 3, in a coagulating solution that coagulates the swollen plastic.

This application is a continuation of U.S. application Ser. No.12/864,781, filed Sep. 20, 2010 which is a national stage entry ofPCT/JP2008/002717, filed Sep. 29, 2008, which claims benefit to JapanesePatent Application No. 2008-016780, filed Jan. 28, 2008, the entirecontents of each of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to an article with a foamed surface, animplant and a method of producing them. More particularly the presentinvention relates to an article with a foamed surface which showsmechanical properties similar to those of bone or teeth when appliedespecially to an implant, and has a surface structure into which bonetissue easily penetrated when implanted in the body of a livingorganism; an implant; and a method of producing them.

BACKGROUND ART

When a large part of bone is lost, employed as a medical treatment isbone autotransplantation in which apiece of bone is removed from apatient's own normal bone and grafted into the bone defect, orartificial bone implantation in which a piece of artificial bone made ofan artificial material is implanted into the defect. However, a limitedamount of harvested bone imposes limitations on boneautotransplantation. Besides, bone autotransplantation falls heavily onthe body of the patient because normal cells are damaged during surgery.In addition, because the removal of apiece of bone to be utilized forautologous bone grafting from a patient's own normal bone creates a newdefect in the bone, this method cannot be an essential treatment whenthe amount of missing bone is large. On the other hand, artificial boneimplantation does not have problems that bone autotransplantation has,because the former employs industrially manufactured artificial bone.However the mechanical and biological properties of artificial bone aredifferent from those of natural bone, the properties of an artificialbone place limitations on the use thereof. For example, artificial bonemade of metal materials such as titanium alloy, which normally have highstrength while having a large coefficient of elasticity and lackingtoughness, causes stress shielding due to differences in mechanicalproperties between the metal material and the surrounding bone, when theartificial bone is implanted in parts that are continuously under greatload. Another problem of artificial bone is that it is not directlyintegrated into natural bone. On the other hand, artificial bone made ofbioceramics such as hydroxyapatite, is usually highly biocompatible aswell as highly bioactive and excellent in binding with natural bone,while it is weak against external impact. Thus it is not suitable to useat parts or places that tend to receive large load in a moment.

The selection of polymers such as ultra high molecular weightpolyethylene for a material of artificial bone solves the problems thatmetal materials and bioceramics have. In particular,polyetheretherketone, which is often abbreviated to PEEK, has mechanicalproperties close to the mechanical properties of natural bone, and PEEKis also excellent in biocompatibility. Therefore its adaptation toorthopedic materials used at parts that require high strength isexpected. Furthermore, artificial bone made of a combined material ofpolymer and bioceramics with biological activity, capable of directlybinding with the native bone, has been developed.

On the other hand, it is well known that the structure of artificialbone, as well as chemical properties such as biocompatibility andbiological activity and physical properties such as strength and elasticmodulus, is an important factor from the viewpoint of binding capabilitywith the native bone. Developed are many artificial bones whose surfaceor entire structure is made porous to facilitate penetration of thebiological tissue into the inside thereof when it is implanted in thebody of a living organism. Innovative approaches to providing artificialbone made of polymeric materials including PEEK with a poroussuperficial layer or a convexo-concave surface have been made in orderto make the best use of its strength and to make it have bindingcapability with native bone.

Patent document 1 discloses an artificial acetabular cup including alining layer, which has a porous structure made by sputtering PEEKparticles with a plasma torch, against a bearing superficial layer madeof a composite material of PEEK and carbon short fibers.

Patent document 2 teaches a sponge-like structure formed by a pluralityof polymer sheets each with at least one aperture wherein the polymersheets are stacked up and stuck together with the locations of theapertures shifted with each other.

Patent document 3 discloses an orthopedic tool, capable of beingimplanted, having a porous organic polymer layer with desired pores. Themethod of forming the porous organic polymer layer comprises embedding apore-forming agent in a polymeric material, allowing the organic polymerto contact a solvent for eluting the pore-forming agent in order to makethe solvent to elute the agent and form desired pores.

Patent document 4 teaches an orthopedic implant formed from athermoplastic resin with a convexo-concave surface wherein theconvexities and concavities are formed by etching, sand blasting,grinding or other methods.

Patent document 5 discloses a method of heat molding a thermoplasticmaterial with a mold having concavities and convexities in the innerwalls thereof.

Patent document 6 teaches a method of decalcomania transferring ofconcavities and convexities in the surface of a surgical implantcomprising press-fitting an acid-soluble metal plate with apredetermined shape into the surface of the surgical implant made of athermoplastic resin, and dissolving the acid-soluble plate.

However, the conventional methods and products have defects: Somerequire expensive apparatuses, like the product of patent document 1;others call for sheet materials to form a porous structure in additionto a polymeric material for parenchyma to realize the strength ofartificial bone, like the product of patent document 2; or still othersneed preparation of polymers including a pore-forming agent, like theproduct of patent document 3. It is easily supposed that the method ofpatent document 4 does not provide sufficient concavities andconvexities suitable to let biological tissue penetrate into theimplant. Furthermore, the methods taught in patent documents 5 and 6 arenot suitable to form a porous structure in the surface of polymericmaterial with a complicated shape.

Also known are methods of making a polymeric material foam therebyforming a porous structure. Among them, one well-known method includessteps of dispersing a solvent with a low boiling point as a foamingagent in a high-molecular weight compound, and heating thehigh-molecular weight compound with the low-boiling-point solventdispersed therein to volatilize or decompose the solvent and then togenerate gas, thereby forming a lot of foam inside the high-molecularweight compound.

Patent document 7 teaches another method including steps of dissolvingan inert gas, such as nitrogen gas or carbon dioxide gas, in athermoplastic resin under a high pressure; releasing the pressure; andheating the thermoplastic resin to a temperature close to its glasstransition temperature, thereby making the gas dissolved in thethermoplastic resin foam to produce a porous material.

As understood, all of the aforementioned methods are those to make ahigh-molecular weight compound in its entirety a porous structure. Sucha porous structure includes pores dispersed all over the structure,which may lower the strength thereof depending on the diameters of thepores and the porosity. Therefore the methods are not suitable toproduce implants to be used at parts that require high strength.

Patent document 1: JP 2006-158953 A

Patent document 2: JP 2006-528515 T

Patent document 3: JP 2004-313794 A

Patent document 4: JP 2001-504008 T

Patent document 5: JP H2(1990)-5425 B

Patent document 6: JP H4(1992)-20353 B

Patent document 7: JP H6(1994)-322168 A

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

A first objective of the present invention is to provide an article witha foamed surface comprising a plastic base with a porous structure inthe surface thereof, the article showing mechanical properties similarto those of bone or teeth when applied especially to an implant, andhaving a surface structure into which bone tissue easily penetrates whenimplanted in a biological body. The present invention also provides animplant.

A second objective of the present invention is to provide a method ofproducing an article with a foamed surface and an implant, capable ofproducing an article with a foamed surface and an implant with acomplicated shape in simple steps.

Means to Solve the Problems

As means to achieve the first objective the present invention provides:

(1) An article with a foamed surface comprising a body and a superficiallayer formed in a surface of the body, the superficial layer includingsmall pores with small diameters and large pores with large diameters,wherein the article is made of a plastic, a part of the small and largepores are open pores which are formed in the surface of the superficiallayer and are open to the outside, the open pores comprise small openpores with an average diameter of 5 μm or less and large open pores withan average diameter from 10 to 200 μm, and the large open pores that arein the surface of the superficial layer have an inner wall with passagesconnected with the small pores and the large pores;

(2) The article with the foamed surface as described under item (1), asa preferable embodiment of the article thereof, wherein the article isapplied to an implant;

(3) The article with the foamed surface as described under item (1) or(2), wherein the plastic is an engineering plastic;

(4) The article with the foamed surface as described under any one ofitems (1)-(3), wherein the plastic is polyetheretherketone;

(5) The article with the foamed surface as described under any one ofitems (1)-(4), wherein the plastic includes at least one fiber selectedfrom the group consisting of carbon fiber, glass fiber, ceramic fiber,metal fiber and organic fiber; and

(6) An implant comprising the article with the foamed surface asdescribed in any one of items (1)-(5), and a bioactive substance on theinner wall of the open pores in the superficial layer of the articleand/or on the surface thereof.

As means to achieve the second objective the present invention provides:

(7) A method of producing an article with a foamed surface including:

step 1 of forming small pores in a surface of a base made of a plasticto produce a base with small pores;

step 2 of immersing the base with small pores, obtained in step 1, in asolution including a foaming agent to prepare a foaming agent-includingbase;

step 3 of immersing the foaming agent-including base, obtained in step2, in a foaming solution that makes the plastic swell and the foamingagent foam to prepare a foamed base; and

step 4 of immersing the foamed base, obtained in step 3, in acoagulating solution that coagulates the swollen plastic.

(8) The method as described under item (7), as a preferable embodimentthereof, further comprising applying the article with the foamed surfaceto an implant.

(9) The method as described under item (7) or (8), wherein the plasticis an engineering plastic;

(10) The method as described under any one of items (7)-(9), wherein theplastic is polyetheretherketone;

(11) The method as described under any one of items (7)-(10), whereinthe plastic includes at least one fiber selected from the groupconsisting of carbon fiber, glass fiber, ceramic fiber, metal fiber andorganic fiber;

(12) The method as described under any one of items (7)-(11), whereinthe foaming solution used in step 3 is concentrated sulfuric acid;

(13) The method as described under any one of items (7)-(12), wherein aporous structure formed in a superficial layer of the foamed article iscontrolled by changing at least one of a kind of the coagulatingsolution, a concentration of the coagulating solution and a time periodfor which the foamed base is immersed in the coagulating solution;

(14) The method as described under any one of items (7)-(13), whereinthe coagulating solution is at least one selected from the groupconsisting of water and a slow coagulating solution which takes a longertime to coagulate the swollen plastic than water;

(15) The method as described under any one of items (7)-(14), whereinthe slow coagulating solution is a solution of sulfuric acid whoseconcentration is less than 90%;

(16) The method as described under any one of items (7)-(15), whereinthe foaming agent is a carbonate;

(17) The method as described under any one of items (7)-(16), whereinthe carbonate includes at least one carbonate compound selected from thegroup consisting of sodium hydrogen carbonate, sodium carbonate andpotassium carbonate; and

(18) A method of producing an implant comprising immersing an articlewith a foamed surface prepared by the method as described in any one ofitems (7)-(17) both in a first solution including calcium ions and asecond solution including phosphate ions wherein the article may befirst immersed in either of the first and second solutions.

Advantages of the Invention

The article with the foamed surface of the present invention is anarticle comprising a body and a superficial layer formed in a surface ofthe body, the superficial layer including small pores with smalldiameters and large pores with large diameters, wherein the article ismade of a plastic, a part of the small and large pores are open poreswhich are formed in the surface of the superficial layer and are open tothe outside, the open pores include small open pores with an averagediameter of 5 μm or less and large open pores with an average diameterfrom 10 to 200 μm, and the large open pores that are in the surface ofthe superficial layer have an inner wall with passages connected withthe small pores and the large pores. When this surface foamed article isapplied to an implant, the article with the foamed surface of thepresent invention, which has many open pores that are open to theoutside in the surface of the superficial layer and passages connectingthese open pores with the small and large pores formed inside thesuperficial layer, is capable of letting native bone tissue penetrateinto the inside of the superficial layer after the article is implantedin the body of a living organism. As a result, new natural bone isformed so that spaces existing in the inside of the superficial layerare filled, which new natural bone makes it possible to integrate thearticle into the native bone. Furthermore, the article with the foamedsurface of the present invention does not have pores all through thevolume, but have many pores in the surface thereof, which makes thearticle to have a strength suitable for a part in which it is implanted.

For the material of this article with a foamed surface, desirable is anengineering plastic, more desirable polyetheretherketone, most desirablea plastic including at least one fiber selected from the groupconsisting of carbon fiber, glass fiber, ceramic fiber, metal fiber andorganic fiber. The employment of these materials will provide thearticle with high strength. When this article is applied to an implant,the implant will have mechanical properties similar to those of bone orteeth. Therefore this article with the foamed surface, when it isimplanted as artificial bone in parts which require integration with thenative bone and continuously bear large load, provides a high-strengthimplant without stress shielding, or possible reduction in the amount ofbone and decrease in the density thereof, caused by shielding of stressapplied to bone.

When the article with a foamed surface has a bioactive substance on theinner walls of open pores in the superficial layer thereof and/or on thesurface of the superficial layer, a chemical reaction takes placebetween the bioactive substance and bone tissue of the living organism,which expedites formation of new natural bone and results in a quickintegration of the implant with the native bone.

The method of producing an article with a foamed surface according tothe present invention has step 1 of forming small pores in a surface ofa base made of a plastic to produce a base with small pores; step 2 ofimmersing the base with small pores, obtained in step 1, in a solutionincluding a foaming agent to prepare a foaming agent-including base;step 3 of immersing the foaming agent-including base, obtained in step2, in a foaming solution that makes the plastic swell and the foamingagent foam to prepare a foamed base; and step 4 of immersing the foamedbase, obtained in step 3, in a coagulating solution that coagulates theswollen plastic. Almost all the steps are thus carried out in a liquidphase. Therefore the method does not require special apparatuses and itis capable of easily producing articles with a foamed surface that evenhave a complicated shape.

For the material of the base, desirable is an engineering plastic, moredesirable polyetheretherketone, most desirable a plastic including atleast one fiber selected from the group consisting of carbon fiber,glass fiber, ceramic fiber, metal fiber and organic fiber. Theemployment of these materials for the base will facilitate theproduction of a surface foamed article with high strength.

Also noticeable is that only changing at least one element selected fromthe group consisting of a kind of the coagulating solution, aconcentration of the coagulating solution and a time period for whichthe foamed base is immersed in the coagulating solution leads to theproduction of an article with a foamed surface whose superficial layerhas a controlled and desired porous structure.

The method of producing an implant according to the present invention isessentially the same as that of an article with a foamed surface asexplained hereinbefore because the former utilizes an article with afoamed surface as an implant as it is. Alternatively, the method ofproducing an implant further includes a step of immersing the articleprepared by the latter method both in a first solution including calciumions and a second solution including phosphate ions wherein the articlemay be first immersed in either of the first and second solutions. Bothmethods are capable of being carried out in a liquid phase, which makesit possible to easily produce implants even with a complicated shape.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic illustration of an article with a foamedsurface according to the present invention.

FIG. 2 Each of FIG. 2A and FIG. 2B (also referred herein as FIGS. 2(a)and 2(b), respectively) shows a schematic illustration of an implanthaving a bioactive substance.

FIG. 3 is a photograph of the surface of the article with the foamedsurface prepared in Working Example 1, obtained with a scanning electronmicroscope.

FIG. 4 is a photograph of a section of the article with the foamedsurface prepared in Working Example 1, obtained with a scanning electronmicroscope.

FIG. 5 is a photograph of the surface of the article with the foamedsurface prepared in Working Example 2, obtained with a scanning electronmicroscope.

FIG. 6 is a photograph of the surface of the article with the foamedsurface prepared in Working Example 3, obtained with a scanning electronmicroscope.

FIG. 7 is a photograph of the surface of the article with the foamedsurface prepared in Working Example 4, obtained with a scanning electronmicroscope.

FIGS. 8A and 8B (also referred herein as FIGS. 8(a) and 8(b),respectively) are photographs of the surface of the article with thefoamed surface prepared in Working Example 5, obtained with a scanningelectron microscope.

FIGS. 9A and 9B (also referred herein as FIGS. 9(a) and 9(b),respectively) are photographs of the surface of the article with thefoamed surface prepared in Working Example 6, obtained with a scanningelectron microscope.

FIGS. 10A and 10B (also referred herein as FIGS. 10(a) and 10(b),respectively) are photographs of the surface of the article with thefoamed surface prepared in Working Example 7, obtained with a scanningelectron microscope.

FIGS. 11A and 11B (also referred herein as FIGS. 11(a) and 11(b),respectively) are photographs of the surface of the article with thefoamed surface prepared in Working Example 8, obtained with a scanningelectron microscope.

FIGS. 12A and 12B (also referred herein as FIGS. 12(a) and 12(b),respectively) are photographs of the surface of the article with thefoamed surface prepared in Working Example 9, obtained with a scanningelectron microscope.

FIG. 13 is a photograph of a section of the article with the foamedsurface prepared in Working Example 9, obtained with a scanning electronmicroscope.

FIGS. 14A and 14B (also referred herein as FIGS. 14(a) and 14(b),respectively) are photographs of the surface of the article with thefoamed surface prepared in Working Example 10, obtained with a scanningelectron microscope.

FIG. 15 is a photograph of the surface of the implant with a bioactivesubstance prepared in Working Example 11, obtained with a scanningelectron microscope.

BEST MODE TO CARRY OUT THE INVENTION

An example of the article with the foamed surface according to thepresent invention will be explained hereinafter, with FIG. 1 referredto. As shown in FIG. 1, an article with a foamed surface 1 of thepresent invention is one having a body 2 and a superficial layer 5, thesurface of which includes many small pores with small diameters 3 andlarge pores with large diameters 4. The article 1 is made of a plastic.Part of the small pores 3 and the large pores 4 are open pores 6 whichare in the surface of the superficial layer 5 and are open to theoutside. The open pores 6 include small open pores 13 with an averagediameter A of not more than 5 μm and large open pores 14 with an averagediameter B from 10 to 200 μm. The large open pores 14, which are in thesurface of the superficial layer and open to the outside, have an innerwall with passages 7 communicating with the small pores 3 and the largepores 4.

The superficial layer 5 includes a plurality of small pores 3 and largepores 4 with different pore sizes. These pores include isolated pores 8that exist in isolation and connected pores 9 formed by two or moreisolated pores connected with each other. Part of the small pores 3 andlarge pores 4 are open pores 6 which are in the surface of thesuperficial layer 5 and are open to the outside. The open pores 6include small open pores 13 with an average diameter A of not more than5 μm, preferably not more than 3 μm, and large open pores 14 with anaverage diameter B from 10 to 200 μm, preferably from 30 to 150 μm. Thelarge open pores 14 have an inner wall with passages 7 connected andcommunicating with the small pores 3 and the large pores 4. One openpore 6 should preferably have more than one passage 7, or it should haveone or more small-diameter passages 15 and one or more large-diameterpassages 16. The small-diameter passage, which connects the open porewith a small pore 3, has a diameter C of not more than 5 μm, preferablynot more than 3 μm. The large-diameter passage, which connects the openpore with a large pore 4, has a diameter D from 10 to 200 μm, preferablyfrom 30 to 150 μm. The small and large pores are in the shape of asphere, a flat sphere, an ellipsoid and/or a combination thereof. Whenan article with a foamed surface 1 according to the present inventionis, for example, implanted in the body of a living organism as animplant, the superficial layer with such pores enables bone tissue, suchas osteoblasts and osteoclasts, to penetrate into the inside of thesuperficial layer 5 through many open pores 6, which are in the surfaceof the superficial layer 5 and open to the outside, and passages 7,which connect the open pores 6 with small pores 3 and large pores 4formed in the inside of the superficial layer. As a result, new naturalbone is formed so that spaces existing in the inside of the superficiallayer are filled. An implant capable of being integrated with nativebone is thus provided. The more the large open pores 14 have passages 7,especially large-diameter passages 16, in the inner walls thereof, thedeeper bone tissue is allowed to penetrate into the superficial layer 5from the surface thereof and to let new born grow deep in thesuperficial layer 5, which leads to strong binding of the implant withthe native bone.

The average diameter of the small open pores 13 and that of the largeopen pores 14 in the surface of the superficial layer 5 may becalculated based on images of the surface obtained through observationwith a scanning electron microscope.

Firstly, a SEM image of the surface of a superficial layer 5 is obtainedwith a scanning electron microscope with a magnification set to, forexample, 300 times. Then, a long diameter and a short diameter ofrelatively large open pores, for example those with the average diameterof about 10 μm or more, in the most superficial part of the layer, foundwithin the entire visual field of the SEM image, are measured.Calculation of the arithmetic average of the measured values providesthe average diameter of the large open pores 14.

Small open pores 13 normally exist in the framework between large openpores 14. When the diameters of the small open pores 13 are measured,the magnification of the scanning electron microscope should be furtherincreased so that measurement errors will be reduced. For example, SEMimages from a scanning electron microscope with a magnification set to3000 times may be utilized. Then, a long diameter and a short diameterof the open pores in the framework are measured. In other words, a longdiameter and a short diameter of all the open pores other than the largeopen pores 14 previously measured are measured. Calculation of thearithmetic average of the measured values provides the average diameterof the small open pores 13.

When the number of large open pores 14 or that of small open pores 13 ona SEM image is large, such as 50 or more, five straight lines should berandomly drawn across the SEM image first. Then, large open pores 14 orsmall open pores 13 on the lines are selected according to the criteriaexplained hereinbefore, and a long diameter and a short diameter thereofare measured. Calculation of the arithmetic average of the measuredvalues provides the average diameter of the large open pores 14 or thesmall open pores 13.

The diameter of a passage 7, which is formed through connections of anopen pore 6, open at the surface of the superficial layer 5, with smallpores 3 and large pores 4, is measured from a SEM image with apredetermined magnification, in the same way as explained above. Anothermethod may be a measurement with a mercury porosimeter.

There is no special limitation on the percentage of the area of thelarge open pores 14 in the most superficial part of the superficiallayer 5 within a projected image of the most superficial part. When asurface foamed article of the present invention is utilized as animplant, however, the percentage should preferably be within a range of10 to 95%, with a particularly preferable range of 20 to 85%. When thepercentage of the area of the large open pores 14 are within thepreferable range, the implant is capable of letting bone tissue into theinside of the superficial layer 5, which allows new bone to grow insidethe superficial layer 5. As a result, an implant capable of binding withthe native bone is provided.

The percentage of the area of the large open pores 14 in the mostsuperficial part of the superficial layer 5 within a projected image ofthe most superficial part may be obtained in the following way: Aphotograph taken with a scanning electron microscope of the surface of asuperficial layer 5 is made binary with an image processing software(e.g. “Scion Image” produced by Scion Corporation), into large openpores 14, or large pores 4 in the surface and open to the outside, andportions other than the large open pores. Calculation of the proportionof the area of the large open pores to that of the entire photographprovides the percentage.

There is no special limitation on the porosity of the small pores 3 andthat of the large pores 4 in the superficial layer. However, theporosity of the small pores 3 should preferably be from 5 to 50%,particularly preferably from 10 to 40%, and the porosity of the largepores 4 should preferably be from 20 to 90%, particularly preferablyfrom 30 to 80%, under the condition that the porosity of the sum of thesmall pores 3 and the large pores 4 be 99% or less. When the porosity ofthe small pores 3 is within the preferable range, the implant has manyscaffolds to which substances involved in osteogenesis, such as proteinsand cells, adhere, which facilitates the formation of new bone in theinside of the superficial layer. As a result, the article with thefoamed surface 1 is strongly bound with the native bone. When theporosity of the large pores 4 is within the preferable range describedabove, bone tissue, after penetrating into the inside of the superficiallayer 5, is easily kept in it, and spaces in which new bone is generatedare ensured. New bone grows so as to fill the spaces with itself, whichfurther strengthens the binding of the implant with the bone.

The porosity of the small pores 3 and that of the large pores 4 in thesuperficial layer 5 were obtained in the following way: A photographtaken with a scanning electron microscope of a section perpendicular tothe surface of the superficial layer 5 is analyzed with an imageprocessing software (e.g. “Scion Image” produced by Scion Corporation),so that the total area of the large pores 4 and that of the small pores3 are respectively calculated. The porosities are obtained from thiscalculation. Images should be obtained by a scanning electron microscopewith a magnification suitable to measure the area of the large pores 4and that of the small pores 3, in the same way as in the calculation ofthe average diameters described hereinbefore. The proportion (a) of thearea of the large pores to that of the entire image provides theporosity of the large pores (a×100(%)). The proportion (b) of the areaof the small pores to that of the area of the entire image except thelarge pores provides the porosity of the small pores ((1-a)×b×100(%)).

The thickness of the superficial layer 5 is suitably decided dependingon the part to which an article with a foamed surface 1 of the presentinvention is applied. For example, when an article with a foamed surface1 of the present invention is used as an implant, the thickness shouldpreferably be in a range of 10 to 1000 μm, particularly preferably in arange of 20 to 200 μm. The thickness within the preferable range allowsbone tissue to penetrate into the inside of the superficial layer 5 frommany open pores 6, which have openings in the surface of the superficiallayer 5, through passages 7, which connect the open pores 6 with smallpores 3 and large pores 4 formed in the inside of the superficial layer,once the implant is embedded in the body of a living organism. As aresult, new bone generates and grows inside the superficial layer 5,which provides an implant capable of being bound with the native bone.

The material for the article with the foamed surface 1 of the presentinvention includes commonly used plastic. When the article 1 of thepresent invention is used as an implant, the material for the article 1should preferably be a plastic whose mechanical properties are similarto those of bone or teeth. Specifically, the plastic should preferablyhave an elastic modulus from 1 to 50 GPa, and a flexural strength from100 MPa or more.

The plastic whose mechanical properties are similar to those of bone orteeth includes engineering plastic or fiber-reinforced plastic. Examplesof the engineering plastic may include polyamide, polyacetal,polycarbonate, polyphenylene ether, polyester, poly(phenylene oxide),poly(butylene terephthalate), poly(ethylene terephthalate), polysulfone,poly(ethersulfone), poly(phenylene sulfide), polyallylate, poly(etherimide), poly(etheretherketone), poly(amide imide), polyimide,fluororesin, ethylene-vinylalcohol copolymer, poly(methyl pentene),phenol resin, epoxy resin, silicone resin, diallyl phthalate resin,polyoxymethylene, and polytetrafluoroethylene.

Plastic for the matrix of the fiber-reinforced plastic may include, inaddition to the engineering plastics listed above, for example,polyethylene, poly(vinyl chloride), polypropylene, EVA resin, EEA resin,4-methylpentene-1 resin, ABS resin, AS resin, ACS resin, methylmethacrylate resin, ethylene-vinyl chloride copolymer, propylene-vinylchloride copolymer, vinylidene chloride resin, poly(vinyl alcohol),poly(vinyl formal), poly(vinyl acetoacetal),poly(fluoroethylene-propylene), polytrifluorochloroethylene,methacrylate resin, polyaryletherketone, polyethersulfone, poly(ketonesulfide), polystyrene, polyaminobismaleimide, urea resin, melamineresin, xylene resin, isophthalic acid resin, aniline resin, furan resin,polyurethane, alkylbenzene resin, guanamine resin, and poly(diphenylether) resin.

When the article with the foamed surface 1 of the present invention isused as an implant, among those substances, poly(etheretherketone),which may sometimes be abbreviated to “PEEK” hereinafter, isparticularly preferable for the material from which the article 1 isformed. PEEK has biocompatibility and mechanical properties close tothose of bone. Therefore the employment of PEEK as material for thearticle with the foamed surface 1 provides, when the article isimplanted as artificial bone in parts continuously bearing large load, ahigh-strength implant without stress shielding, or possible reduction inthe amount of bone and decrease in the density thereof, caused byshielding of stress applied to bone.

The fiber for the fiber-reinforced plastic may include carbon fiber,glass fiber, ceramic fiber, metal fiber and organic fiber. The carbonfiber for this invention includes carbon nanotubes. Examples of theglass fiber may include fibers of borosilicate glass (E Glass), highstrength glass (S Glass), and high-elasticity glass (YM-31A glass). Theceramic fiber may include fibers of silicon carbide, silicon nitride,alumina, potassium titanate, boron carbide, magnesium oxide, zinc oxide,aluminum borate, boron and the like. Examples of the metal fiber mayinclude fibers of tungsten, molybdenum, stainless steel and tantalum.Examples of the organic fiber may include fibers of polyvinyl alcohol,polyamide, polyethylene terephthalate, polyester, aramid, and mixturesthereof.

The material for the surface foamed article 1 may include, if necessary,various additives such as an antistatic agent, an antioxidant, a lightstabilizer such as hindered amine compounds, a lubricant, ananti-blocking agent, an ultraviolet absorber, an inorganic filler, and acolorant such as a pigment.

When the article with the foamed surface 1 of the present invention isused as an implant, the inner walls of the open pores 6 in thesuperficial layer 5 and/or the surface of the superficial layer 5 shouldpreferably be provided with a bioactive substance. If a bioactivesubstance is carried on the inner walls and/or the surface, a chemicalreaction takes place between the bioactive substance and bone tissue ofthe living organism once the implant is embedded in the body of a livingorganism, which expedites formation of new natural bone and results in aquick integration of the implant with the native bone.

FIGS. 2(a) and 2(b) show schematic illustrations of implants with abioactive substance. As shown in FIG. 2(a), a bioactive substance 210 amay be formed on the entirety of the inner walls 211 a of the open pores206 a in the superficial layer 205 a and on the entirety of the surfaceof the superficial layer 205 a. As shown in FIG. 2(b), a bioactivesubstance 210 b may be formed on parts of the inner walls of the openpores 206 b and/or parts of the surface of the superficial layer 206 b.When the inner walls 211 a, 211 b of the open pores 206 a, 206 b areprovided with the bioactive substance 210 a, 210 b, the substance 210 a,210 b should not be formed in such a way that all the open pores 206 a,206 b are completely filled with the substance; as shown in FIGS. 2(a)and 2(b), part or all of the inner walls 211 a, 211 b of the open pores206 a, 206 b should be covered with the bioactive substance 210 a, 210b. For example, as shown in FIG. 2(a), a small open pore 213 a may becompletely filled with the bioactive substance 210 a, whereas a largeopen pore 214 a should preferably have the inner wall 214 a thereofcoated with the bioactive substance 210 a, with the volume of the largeopen pore 214 a kept essentially unchanged. In addition, alarge-diameter passage 216 a, which connects the large open pore with alarge pore 204 a, should not be stopped up with the bioactive substance210 a but should have a diameter D large enough to let bone tissue passthrough the passage. An implant 212 a having a superficial layer 205 awith open pores 206 a which communicate with the inner part of the layerthrough the large-diameter passage 216 a, after the implant 212 a isembedded in the body of a living organism, allows bone tissue topenetrate into the inside of the superficial layer 205 a from the openpores 206 a. As a result, a chemical reaction takes place between thebioactive substance 210 a on the inner walls 211 a of the open pores 206a and bone tissue of the living organism, which leads to the generationof new bone. The new bone grows so that the large open pore 214 a, asmall pore 203 communicating with the large open pore 214 a, and thelarge pore 204 a are filled with the new bone. Therefore new bone aswell as the bioactive substance grows and spreads out in a complicatedarborescent shape in the inside of the superficial layer 205 a. Insummary, when an implant has an open pore 206 a, which is in the surfaceof the superficial layer 205 a and is open to the outside, and a passage207 a, especially a large-diameter passage 216 a, communicating with theopen pore 206 a, and a bioactive substance 210 a on the inner wall 211 aof the open pore 206 a, the binding of the implant 212 a with bone isexpedited and strengthened.

When the respective images of the superficial layers 205 a, 205 b areprojected, the proportion of the area of the wall and surface coveredwith the bioactive substance 210 a, 210 b should preferably be at least5%, particularly preferably 20% or more within the projected images. Inthis context, the bioactive substance 210 a, 210 b includes not only thesubstance on the surface of the superficial layer 205 a, 205 b but alsothe substance on the inner wall 211 a, 211 b of the open pore 206 a, 206b, capable of being recognized by the eye from the outside of thesuperficial layer 205 a, 205 b. When an implant includes the bioactivesubstance 210 a, 210 b on the inner wall 211 a, 211 b of the open pore206 a, 206 b in the superficial layer 205 a, 205 b and/or on the surfaceof the superficial layer 205 a, 205 b, at a proportion within thepreferable range mentioned above, a chemical reaction takes placebetween the bioactive substance 210 a, 210 b and bone tissue of a livingorganism once the implant is embedded in the body of the livingorganism, which expedites formation of new natural bone and results in aquick binding of the implant 212 a, 212 b with the native bone.

When the respective images of the superficial layers 205 a, 205 b areprojected, the proportion of the area of the wall and surface coveredwith the bioactive substance 210 a, 210 b within the projected imagesmay be obtained in the following way: An image taken with a scanningelectron microscope of the surface of a superficial layer 205 a or 205 bis made binary with an image processing software (e.g. “Scion Image”produced by Scion Corporation), or into portions with the bioactivesubstance 210 a, 210 b and other portions. Calculation of the proportionof the area of the portions with the bioactive substance to that of theentire image provides the percentage.

The implant should include the bioactive substance 210 a, 210 b at aproportion from 0.5 to 30% to the volume of the superficial layer 205 a,205 b. The bioactive substance 210 a, 210 b exists in separate spots onthe inner walls 211 a, 211 b of the open pores 206 a, 206 b in thesuperficial layer 205 a, 205 b, and/or on the surface of the superficiallayer 205 a, 205 b, and/or in the inside of the superficial layers 205,205 b; and/or these spots of the bioactive substance 210 a, 210 b arelinked together so that the substance stretches into the inside of thesuperficial layers 205 a, 205 b in the shape of tree branches. Once theimplant 212 a, 212 b with the bioactive substance 210 a, 210 b in therange of the amount described above in the superficial layer 205 a, 205b is embedded in the body of a living organism, a chemical reactiontakes place between the bioactive substance 210 a, 210 b and bone tissueof the living organism, which expedites formation of new natural boneand results in a quick integration of the implant 212 a, 212 b with thenative bone.

The proportion of the volume of the bioactive substance 210 a, 210 bincluded in the superficial layer 205 a, 205 b may be obtained by amethod similar to the method to obtain the proportion of the area of thebioactive substance 210 a, 210 b explained hereinbefore. Specifically,the proportion of the area of the bioactive substance 210 a, 210 b in asection perpendicular to the surface of the superficial layer 205 a, 205b is calculated first. Then, the proportion of the volume of thebioactive substance 210 a, 210 b can be estimated based on thecalculated values.

There is no special limitation on the bioactive substance 210 a, 210 bif it has high affinity with living organisms and it is capable ofchemically reacting with bone tissue including teeth. Examples of such asubstance may include calcium phosphate materials, bioglass,crystallized glass, which is also called “glass-ceramic”, and calciumcarbonate. Specific examples of the calcium phosphate materials mayinclude calcium hydrogen phosphate, dibasic calcium phosphate hydrate,calcium dihydrogen phosphate, monobasic calcium phosphate hydrate,α-tricalcium phosphate, β-tricalcium phosphate, dolomite,tetracalciumphosphate, octacalciumphosphate, hydroxyapatite,fluoroapatite, carboxyapatite, and chlorapatite. Specific examples ofthe bioglass may include SiO₂—CaO—Na₂O—P₂O₅ glass,SiO₂—CaO—Na₂O—P₂O₅—K₂O—MgO glass, and SiO₂—CaO—Al₂O₃—P₂O₅ glass.Specific examples of the crystallized glass may includeSiO₂—CaO—MgO—P₂O₅ glass, which is also called “apatite-wollastonitecrystallized glass”, and CaO—Al₂O₃—P₂O₅ glass. These calcium phosphatematerials, bioglass and crystallized glass are explained in detail inbooks such as “Chemical Handbook, the Volume of Adapted Chemistry”edited by the Chemical Society of Japan, published on Jan. 30, 2003 byMARUZEN Co., Ltd.; and “Clinical Application and Development ofBioceramics” written and edited by Hideki Aoki et al., published on Apr.10, 1987 by Quintessence Publishing Co., Ltd.

Among these materials, the calcium phosphate materials are preferablefor the bioactive substance 210 a, 210 b because of their excellence inbioactivity. Especially preferable is hydroxyapatite because it isexcellent in stability in the body due to its resemblance to naturalbone in structure and properties, and it does not show a remarkablesolubility in the body.

Also, the bioactive substance 210 a, 210 b should preferably be low incrystallinity. The term “low in crystallinity” in this context means astate where the growth of the crystal is at a low degree. In the case ofhydroxyapatite, the term means hydroxyapatites with scattering angles2θ=25.878° and the full width at half maximum of 0.2° or more in thespacing of lattice planes (d value) of 3.44 Å. Because thehydroxyapatite of bone is low in crystallinity wherein the full width athalf maximum is about 0.4° under the above-mentioned conditions, abioactive substance with a similar crystallinity, specifically with afull width at half maximum from 0.2 to 1° under the above-mentionedconditions, realizes a quick integration of the implant with the nativebone.

When the bioactive substance is formed by a method which includes, forexample, immersing the article with the foamed surface in a solutionhaving calcium or phosphine, modifications to the kinds of components ofthe solution, the composition thereof, and/or the temperature at whichthe article is immersed in the solution will be able to adjust thecrystallinity of the bioactive substance 210 a, 210 b.

An example of the method of producing an article with a foamed surfaceaccording to the present invention will be explained in the following.

Step 1 of the method includes preparation of a base with small pores,which has many small pores in the surface of the base made of a plasticmaterial with a predetermined shape. For forming small pores in thesurface of the plastic may be employed known methods. One of the knownmethods includes, for example, immersing a base made of a plastic in acorrosive solution, such as concentrated sulfuric acid, concentratednitric acid or chromic acid, for a predetermined period of time; andthen immersing the plastic base treated in the previous step in awashing solution that does not dissolve the plastic, such as pure water.When for example polyetheretherketone (PEEK) is employed for theplastic, the immersion of a PEEK base in concentrated sulfuric acid andsubsequently in pure water is capable of forming small pores in thebase.

The pores formed in the surface of the plastic base should have such adiameter as to enable a foaming agent to be used in step 2 to penetrateinto the inside of the plastic base. The diameter may be suitably chosendepending on the kind of foaming agent. When for example sodiumcarbonate is employed for the foaming agent, the diameter of the smallpores should preferably be from 0.1 to 200 μm. The surface of theplastic base should include small pores at such a porosity that they arecapable of sufficiently holding the foaming agent to be used in step 2.When the foaming agent is, for example, sodium carbonate, the layer ofthe plastic base in which small pores are formed should preferably havea porosity of the range of 10 to 90%. When the porosity has a smallervalue within the range, each pore should be formed so that a foamingagent will be held at a desired depth from the surface of the plasticbase; a plurality of connected pores may be formed from the surface ofthe plastic base toward the inside thereof; or columnar poresperpendicular to the surface of the base may extend from the surface ofthe plastic base to the inside thereof. The layer with many pores formedtherein should have a thickness roughly the same as that of the articlewith the foamed surface, the final product. Specifically, the thicknessshould be preferably from 10 to 1000 μm. When the corrosive solution forPEEK is for example concentrated sulfuric acid, modifications to a timeperiod for and/or a temperature at which the PEEK base is immersed inconcentrate sulfuric acid may be used to control the thickness of thelayer with many pores. Also, modifications to the kind of the washingsolution and/or the temperature at which the article is immersed in thewashing solution after the immersion in the concentrated sulfuric acidwill be able to adjust the diameter of the pores and the porosity.

Step 2 includes immersing the base with small pores prepared in step 1in a solution including a foaming agent for a predetermined period oftime, thereby preparing a foaming agent-holding base, which holds thefoaming agent at the surface of the base with many small pores. Thefoaming agent may be anything as long as it is a substance capable offorming a desired porous structure at the surface of the plastic base.Examples of the foaming agent may include inorganic foaming agents suchas carbonate salts and aluminum powder, and organic foaming agents suchas azo compounds and isocyanates. When the article with the foamedsurface, which is the final product, is applied to an implant, thefoaming agent should be a substance that is harmless to livingorganisms. Carbonates are preferably used as the harmless foaming agent.Examples of the carbonates may include sodium bicarbonate, sodiumcarbonate and potassium carbonate.

Step 3 includes immersing the foaming agent-holding base obtained instep 2 for a predetermined period of time in a foaming solution capableof making the plastic swell and the foaming agent foam, thereby allowingthe swelling and the foaming to progress simultaneously to thepreparation of a foamed base. The foaming solution may include an acidsolution, such as concentrated sulfuric acid, hydrochloric acid andnitric acid. When the foaming agent-holding base is made of PEEK and thefoaming agent is a carbonate, the foaming solution should preferably beconcentrated sulfuric acid with a concentration of 90% or more.

Step 4 prepares an article with a foamed surface, which includesimmersing the foamed base obtained in step 3 in a coagulating solutionthat coagulates the swollen plastic. The coagulating solution, whichmust not dissolve the plastic, may include an aqueous solution such aswater, acetone and ethanol. When the foamed base is made of PEEK, thecoagulating solution may further include an aqueous solution of aninorganic acid such as an aqueous sulfuric acid solution with aconcentration of less than 90%, an aqueous nitric acid solution, anaqueous phosphoric acid solution and an aqueous hydrochloric acidsolution, and a water-soluble organic solvent. Examples of thewater-soluble organic solvent may include N-methyl-2-pyrrolidone;dimethyl formamide; dimethyl acetoamide; dimethyl sulfoxide;tetrahydrofuran; alcohols such as ethylene glycol, diethylene glycol,triethylene glycol, propylene glycol, dipropylene glycol, glycerinethanol, propanol, butanol, pentanol and hexanoyl, and aqueous solutionsthereof; and liquid polymers such as polyethylene glycol, polypropyleneglycol and polyvinyl pyrrolidone, or aqueous solutions thereof andmixtures thereof.

The foamed base obtained in step 3 may be immersed in at least onesolution selected from the kinds of solutions capable of being used forthe coagulating solution, or several kinds of such solutions one by one.Also, a mixture of at least two such solutions may be used for thecoagulating solution.

Preferably substances remaining on the article with the foamed surface,such as the foaming agent and the coagulating solution, should be washedoff with pure water after step 4.

The porous structure formed in the surface of the plastic base, i.e. thediameter of the large open pores, that of the small open pores, that ofthe passages, and the porosity, which define the porous structure of thesuperficial layer of the surface foamed article, may be controlledthrough suitable selection of factors such as the kind and concentrationof the foaming agent, the kind and concentration of the foamingsolution, the time period for which the foaming agent-holding base isimmersed in the foaming solution, the kind and concentration of thecoagulating solution, the time period for which the foamed base isimmersed in the coagulating solution, and the temperature in each step.

If at least one parameter selected especially from the kind of thecoagulating solution, the concentration thereof and the time period forwhich the foamed base is immersed therein, among these parameters, ischanged, it will lead to an easy production of an article with a foamedsurface whose superficial layer has a desired porous structure. Changesin these parameters are capable of controlling the coagulating rate ofthe swollen plastic in the surface of the foamed base. For thecoagulating solution, preferable are water, and at least one slowcoagulating solution which takes a longer time to coagulate the swollenplastic than water. When the material of the foamed base is PEEK, theslow coagulating solution may be an aqueous sulfuric acid solution witha concentration of less than 90%.

When a foamed base made of, for example, PEEK is immersed in, ascoagulating solution, an aqueous sulfuric acid solution with aconcentration of 86%, PEEK coagulates moderately compared with the casewhere the foamed base is immersed in water. In other words, thecoagulating speed is slowed down. This slowness allows the porousstructure in the surface of the foamed base to change with time whilethe foamed base is being immersed in the coagulating solution.

Changes in the structure of the surface of the foamed base caused by adifference in the time period for which the foamed base is immersed in aslow coagulating solution will be explained hereinafter, with alarge-diameter passage 16 formed by the connection of two large pores 4,and with a small pore 3.

The diameter of the large open pores 14, or the large pores 4 which areat the surface and open to the outside, and the diameter of thelarge-diameter passages 16 become larger gradually in course of theperiod of time for which the foamed base is immersed in the coagulatingsolution. After a predetermined period of time, they turn to becomingsmaller. The number of large open pores 14 and large-diameter passages16 decreases in course of the period of time for which the foamed baseis immersed in the coagulating solution. It is supposed that the reasonwhy the diameters become larger with time is that a plurality of poresgenerated by the foaming agent become connected and larger while theswollen PEEK is coagulating moderately. On the other hand, we think thereason why the diameters turn to becoming smaller after a predeterminedperiod of time in the following way: The effect of the foaming agent isweakened while the swollen PEEK is coagulating moderately, which makessmaller the diameter of all the pores including enlarged pores due tothe connection. Also, it is surmised that the reason for the decrease inthe number of large open pores 14 and large-diameter passages 16 incourse of the period of time for which the foamed base is immersed inthe coagulating solution is that large open pores 14 and large-diameterpassages 16 are linked and unified while the swollen PEEK is coagulatingmoderately.

The diameter of the small open pores 13, or the small pores 3 which areat the surface and open to the outside, and the porosity become smallergradually in course of the period of time for which the foamed base isimmersed in the coagulating solution. Large pores are formed by theaction of the foaming agent, whereas it is considered that small poresare formed by phase separation of the swollen PEEK. The phase separationdoes not tend to occur between the swollen PEEK and a slow coagulatingsolution that coagulates the PEEK moderately. It is thought that thelonger the period of time for which the foamed base is immersed in aslow coagulating solution is made, the smaller the number of small openpores 13 and the diameter thereof as well as the porosity are made.

As explained hereinbefore, the difference in the period of time forwhich the foamed base is immersed in a slow coagulating solution maylead to the production of articles 1 with a foamed surface whosesuperficial layers 5 have different porous structures. In particular, ifa foamed base is transferred to a coagulating solution capable ofcoagulating swollen plastic quickly, such as water, at the point of timewhen the diameter of the large open pores 14 and that of thelarge-diameter passages become the largest, the coagulation isimmediately completed, which provides a surface foamed article 1 withgood connection of pores toward the inside of the superficial layer 5.

The explanation that has been made so far takes an 86% aqueous solutionof sulfuric acid as an example of the coagulating solution. When anaqueous solution of sulfuric acid with a less concentration is used as aslow coagulating solution, the manner of changing in the structure atthe surface of a foamed base is different. When an aqueous sulfuric acidsolution with a less concentration is used, the swollen PEEK coagulatesin a shorter period of time than it does when an 86% aqueous sulfuricacid solution is used, which may lead to the coagulation of the largepores 4 before the effect of the foaming agent is weakened. In thiscase, a longtime immersion of the foamed base in the coagulatingsolution will neither make smaller the diameter of the large pores 14and that of the large passages 16 nor the number thereof.

As explained hereinbefore, how the structure at the surface of thefoamed base changes in course of the period of time for which the foamedbase is immersed in the coagulating solution is different depending onthe kind and concentration of the slow coagulating solution. Therefore,if one chooses a desired slow coagulating solution, immerses a foamedbase in it for a predetermined period of time, and transfers the baseinto water at the point of time when the surface of the foamed base hasa desired porous structure, which immediately completes the coagulationof the swollen plastic, an article with a foamed surface whosesuperficial layer 5 has a desired porous structure is obtained. As amethod of coagulating the swollen plastic other than the immersion of itin water, the swollen plastic may be kept in a slow coagulating solutionfor a time period sufficient to coagulate completely.

In the following will be explained an example of the method forproducing an implant with a bioactive substance on the surface of thesuperficial layer and/or in the inside thereof wherein an article with afoamed surface prepared by the method explained hereinbefore is appliedto the implant.

The bioactive substance may be formed by any method as long as it isfixed to the inner walls of open pores in the superficial layer and/oron the surface of the superficial layer. An example of the method may bea liquid phase method in which an article with a foamed surface preparedthrough steps 1-4 is immersed both in a first solution including atleast 10 mM of calcium ions and a second solution including at least 10mM of phosphate ions wherein the article with the foamed surface may befirst immersed in either of the first and second solutions.

An example of the method of producing an implant with the liquid phasemethod will be explained hereinafter.

Firstly, an article with a foamed surface prepared through steps 1-4 isimmersed in a first solution including at least 10 mM of calcium ionsfor a predetermined period of time. There is no special limitation onthe first solution as long as it includes at least calcium ions. Thefirst solution may further include other ions such as sodium ions,potassium ions, magnesium ions, carbonate ions, silicate ions, sulfateions, nitrate ions, chloride ions and hydrogen ions, while preferablythe first solution should substantially not include phosphate ions. Thefirst solution including calcium ions may usually be aqueous solutionsof chemical compounds which have high water-solubility and do not exerta bad influence on the human body. Examples of the first solution mayinclude aqueous solutions of calcium chloride, calcium hydroxide,calcium nitrate, calcium formate, calcium acetate, calcium propionate,calcium butyrate, calcium lactate, and mixed solutions thereof. Amongthem preferable is an aqueous solution of calcium chloride.

After the immersion in the first solution including calcium ions for apredetermined period of time, the article is immersed in a secondsolution including at least 10 mM of phosphate ions. There is no speciallimitation on the second solution as long as it includes at leastphosphate ions. The second solution may further include other ions suchas sodium ions, potassium ions, magnesium ions, carbonate ions, silicateions, sulfate ions, nitrate ions, chloride ions and hydrogen ions, whilepreferably the second solution should substantially not include calciumions. The second solution including phosphate ions may usually beaqueous solutions of chemical compounds which have high water-solubilityand do not exert a bad influence on the human body. Examples of thesecond solution may include aqueous solutions of phosphoric acid,disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassiumhydrogen phosphate, potassium dihydrogen phosphate, and mixed solutionsthereof. Among them preferable is an aqueous solution of dipotassiumhydrogen phosphate.

There is no special limitation on the order of immersion in the twosolutions. However, when hydroxyapatite as bioactive substance isprepared in the inside of the superficial layer, i.e. in the porousstructure, the preparation reaction should proceed in an alkaline mediumwhere hydroxyapatite shows less solubility, from the viewpoint of theproduction amount. Therefore the solution in which the article with thefoamed surface is immersed later should be alkaline, specifically with apH from 8 to 10.

The time period for which the article is immersed in each of the firstsolution including at least calcium ions in an amount of at least 10 mMand the second solution including at least phosphate ions in an amountof at least 10 mM should be preferably from 1 minute to 5 hours,particularly preferably from 3 minutes to 3 hours. The immersion withinthe range of 1 minute to 5 hours enables calcium ions and phosphate ionsto sufficiently permeate into the inside of the article with the foamedsurface, and allows a bioactive substance to be produced on and fixed tothe inner walls of the open pores and passages in the superficial layerof the article. If an increase in the amount of the produced bioactivesubstance is desired, the operation of immersing the article in eachsolution may be carried out several times.

In the final step, the article with the foamed surface carrying thebioactive substance produced therein is washed in pure water and dried.Thus obtained is an implant having an article with a foamed surfacecarrying a bioactive substance on the inner walls of at least open poresin the superficial layer thereof and/or the surface of the superficiallayer thereof.

The method of producing a bioactive substance is not limited to thatexplained above. Another method may include steps of immersing anarticle with a foamed surface in a solution that contains a great amountof a bioactive substance; drying the resulting article, thereby fixingthe bioactive substance onto the inside of the superficial layer havingthe porous structure in the article; washing the resultant in purewater; and drying the obtained again.

The method according to the present invention may be used to producearticles with a foamed surface other than the article 1 of the presentinvention. The produced articles have various uses including implants.When applied to implants, they are used in various shapes, such asgranules, fibers, blocks or films, depending on the parts in the body ofa living organism. Preferably the implant should be formed, correctedand/or made into a shape which is essentially the same as the shape ofthe defective part of bone or a tooth that is about to be filled withthis implant, or a shape which corresponds to the shape thereof, such asa similar shape.

Either a method of forming, correcting and/or making a blank made of aplastic such as PEEK into a plastic base with a desired shape which isfollowed by forming a superficial layer with a porous structure in thesurface of the plastic base, or a method of forming a superficial layerwith a porous structure in the surface of a plastic blank which isfollowed by correcting and/or making the plastic blank into a plasticbase with a desired shape provides an article with a foamed surfaceaccording to the invention. The employment of the liquid phase methoddescribed hereinbefore to prepare an article with a foamed surfacefacilitates a formation of the superficial layer with a porous structurein the surface part of the plastic base after a blank made of a plasticsuch as PEEK is formed, corrected and/or made into a plastic base with acomplicated shape.

The superficial layer may be formed in the entire surface of a plasticbase. Alternatively, when the article with the foamed surface is used asan implant, the superficial layer may be formed only in the parts of thesurface that require bonding with bone or teeth. The article with thefoamed surface may also be applied to an implant with a bioactivesubstance at least on the inner walls of open pores in the superficiallayer and/or on the surface of the superficial layer.

The article with the foamed surface and the implant with a bioactivesubstance may be applied to bone fillers, artificial joints, boneconnecting materials, artificial vertebral bodies, spacers betweenvertebral bodies, cages between vertebral bodies and dental implants.

EXAMPLES

The invention is described by way of working examples, which impose nolimitations on the present invention.

Preparation and Evaluation of Article with Foamed Surface WorkingExample 1

This is a working example in which PEEK was used as material for anarticle with a foamed surface.

The article was prepared through the following steps.

A surface of a disc (with 10 mm in diameter and 2 mm in thickness, a450G product manufactured by Victrex Corporation) was ground with #1000sandpaper. The ground disc was immersed in concentrated sulfuric acidwhose concentration was 97% for five minutes. The disc was taken out ofthe sulfuric acid and then immersed in pure water for five minutes.Subsequently, the disc was repeatedly washed until the pH of pure waterused for the washing turned neutral. A micro-porous base with micropores in the surface thereof was obtained. An observation of the surfaceof the micro-porous base with a scanning electron microscope revealedthat the surface had many pores with a diameter from 1 to 2 μm and theinside of the surface had a network structure.

Then the obtained micro-porous base was immersed in an aqueous solutionof sodium bicarbonate with a concentration of 500 mM for 60 minutes,which allowed the micro-porous base to hold sodium bicarbonate at thesurface thereof. A foaming agent-holding base was thus prepared.

The foaming agent-holding base was immersed for one minute inconcentrated sulfuric acid whose concentration was 97% and which was afoaming solution, which allowed the surface of the PEEK of the foamingagent-holding base to swell and simultaneously the sodium bicarbonateheld by the base to foam. A foamed base was thus prepared.

The foamed base was taken out of the concentrated sulfuric acid. It wasthen immersed in pure water for ten minutes, which coagulated thesurface of the PEEK. The resultant was washed repeatedly until the pH ofpure water used for the washing turned neutral. The washed base wasdried at 120° C. for three hours, which provided an article with afoamed surface.

The surface of the prepared article was observed under a scanningelectron microscope at 300 magnifications. The resulting image is shownin FIG. 3. Many small open pores originating from small pores with adiameter from 1 to 5 μm and many large open pores originating from largepores with a diameter from 50 to 100 μm were observed. Also observedwere many small-diameter passages connecting large open pores with smallpores and many large-diameter passages connecting large open pores withlarge pores in the inner walls of the large open pores.

A long diameter and a short diameter of each of the large open pores andsmall open pores were measured by the method explained hereinbeforebased on a photograph taken with a magnification of 3000 times and aphotograph with a magnification of 300 times. Calculation of thearithmetic average of the measured values provided the average diameterof the small open pores and that of the large open pores: The former was2 μm, and the latter was 73 μm.

A photograph taken with a scanning electron microscope of the surface ofthe surface foamed article was made binary with an image processingsoftware (specifically “Scion Image” produced by Scion Corporation),into large open pores and portions other than the large open pores. Theproportion of the area of the large open pores to that of the entirephotograph was calculated, and it was 78%.

A section perpendicular to the surface of the prepared article wasobserved under a scanning electron microscope at 500 magnifications. Theresulting image is shown in FIG. 4. A layer with a thickness ofapproximately 70 μm that included many pores was observed in the surfaceof the article.

Photographs of a section perpendicular to the surface of a test piece,which was the superficial layer of the prepared article, were taken witha scanning electron microscope with a magnification of 3000 times and amagnification of 300 times. The photographs were processed with an imageprocessing software (“Scion Image” produced by Scion Corporation), andthe total area of the small pores and that of the large pores arerespectively calculated. The porosity of the small pores and that of thelarge pores were calculated respectively from the proportion of the areaof the small pores to that of the entire photograph and the proportionof the area of the large pores to that of the entire photograph, asexplained hereinbefore. As a result, the porosities of the small poresand the large pores were respectively 18% and 64%.

The diameters of the passages in the superficial layer, having manypores, of the prepared article were measured with a mercury porosimeter.It was observed that the amount of mercury injected into the superficiallayer was larger than that of mercury injected into unprocessed controlPEEK, in the diameter range of 1 to 100 μm. This observation meant thatpassages having a diameter in this range were formed with a widedistribution of diameters. This result was consistent with the result ofan observation of the superficial layer with a scanning electronmicroscope.

Working Example 2

An article with a foamed surface was obtained with the same method as inWorking Example 1, except that an aqueous solution of sodium carbonatewhose concentration was 500 mM was used in place of the aqueous solutionof sodium bicarbonate.

The surface of the prepared article was observed under a scanningelectron microscope at 300 magnifications. The resulting image is shownin FIG. 5. Many open pores and many passages formed in the inner wallsof the open pores were observed in the surface of the article, in thesame way as in Working Example 1. Small open pores originating fromsmall pores had a diameter ranging from 2 to 4 μm, and large open poresoriginating from large pores had a diameter ranging from 30 to 80 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 3.1 μm, and the latter was 45 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 39%.

Working Example 3

An article with a foamed surface was obtained with the same method as inWorking Example 1, except that an aqueous solution of potassiumcarbonate whose concentration was 500 mM was used in place of theaqueous solution of sodium bicarbonate.

The surface of the prepared article was observed under a scanningelectron microscope at 300 magnifications. The resulting image is shownin FIG. 6. Many open pores and many passages formed in the inner wallsof the open pores were observed in the surface of the article, in thesame way as in Working Example 1. Small open pores originating fromsmall pores had a diameter ranging from 1 to 2 μm, and large open poresoriginating from large pores had a diameter ranging from 20 to 30 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 1.6 μm, and the latter was 23 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 15%.

Working Example 4

An article with a foamed surface was obtained with the same method as inWorking Example 3, except that the concentration of the aqueous solutionof potassium carbonate was changed to 3 M.

The surface of the prepared article was observed under a scanningelectron microscope at 300 magnifications. The resulting image is shownin FIG. 7. Many open pores and many passages formed in the inner wallsof the open pores were observed in the surface of the article, in thesame way as in Working Example 3. Small open pores originating fromsmall pores had a diameter ranging from 1 to 4 μm, and large open poresoriginating from large pores had a diameter ranging from 100 to 200 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 2.4 μm, and the latter was 106 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 64%.

Working Example 5

An article with a foamed surface was obtained with the same method as inWorking Example 4, except that the foamed base was immersed in anaqueous solution of sulfuric acid with a concentration of 63% for oneminute, after the foamed base was taken out of the concentrated sulfuricacid and before it was immersed in pure water for ten minutes.

The surface of the prepared article was observed with a scanningelectron microscope. An image obtained at 100 magnifications is shown inFIG. 8(a), and an image at 3000 magnifications in FIG. 8(b). As shown inFIG. 8(a), many open pores and many passages formed in the inner wallsof the open pores were observed in the surface of the article, in thesame way as in Working Example 4. The number of passages was essentiallythe same as that of passages in the article obtained in Working Example4. Large open pores originating from large pores had a diameter rangingfrom 10 to 100 μm.

As shown in FIG. 8(b), small open pores originating from small pores hada diameter ranging from 0.2 to 4 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 1.4 μm, and the latter was 39 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 61%.

Working Example 6

An article with a foamed surface was obtained with the same method as inWorking Example 5, except that the period of time for which the foamedbase was immersed in the 63% aqueous solution of sulfuric acid waschanged to five minutes.

The surface of the prepared article was observed with a scanningelectron microscope. An image obtained at 100 magnifications is shown inFIG. 9(a), and an image at 3000 magnifications in FIG. 9(b). As shown inFIG. 9(a), many open pores and many passages formed in the inner wallsof the open pores were observed in the surface of the article, in thesame way as in Working Example 5. The number of passages was a littlesmaller than that of passages in the article obtained in Working Example5. Large open pores originating from large pores had a diameter rangingfrom 30 to 300 μm, which was larger than the diameter of the large openpores included in the article of Working Example 5.

As shown in FIG. 9(b), small open pores originating from small pores hada diameter ranging from 0.5 to 5 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 1.4 μm, and the latter was 118 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 67%.

Working Example 7

An article with a foamed surface was obtained with the same method as inWorking Example 5, except that the period of time for which the foamedbase was immersed in the 63% aqueous solution of sulfuric acid waschanged to 15 minutes.

The surface of the prepared article was observed with a scanningelectron microscope. An image obtained at 100 magnifications is shown inFIG. 10(a), and an image at 3000 magnifications in FIG. 10(b). As shownin FIG. 10(a), many open pores and many passages formed in the innerwalls of the open pores were observed in the surface of the article, inthe same manner as with the article with the foamed surface obtained inWorking Example 5. The number of passages was essentially the same asthat of passages in the article with the foamed surface obtained inWorking Example 6. Large open pores originating from large pores had adiameter ranging from 30 to 300 μm, which was essentially the same asthe diameter of the large open pores included in the article of WorkingExample 6. The reason that the diameter of the large open pores and thenumber of passages were essentially the same as the corresponding valuesin Working Example 6 is considered to be that the coagulation of thefoamed base was almost completed after the foamed base was immersed inthe 63% aqueous solution of sulfuric acid for ten minutes.

As shown in FIG. 10(b), small open pores originating from small poreshad a diameter ranging from 0.5 to 5 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 1.8 μm, and the latter was 122 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 68%.

Working Example 8

An article with a foamed surface was obtained with the same method as inWorking Example 5, except that an aqueous solution of sulfuric acid witha concentration of 86% was used in place of the 63% aqueous solution ofsulfuric acid.

The surface of the prepared article was observed with a scanningelectron microscope. An image obtained at 100 magnifications is shown inFIG. 11(a), and an image at 3000 magnifications in FIG. 11(b). As shownin FIG. 11(a), many open pores and many passages formed in the innerwalls of the open pores were observed in the surface of the surfacefoamed article, in the same manner as with the article with the foamedsurface obtained in Working Example 5. Large-diameter passages, formedby the connection of a large open pore with large pores, had a largerdiameter than the equivalents in the article obtained in Working Example5. The diameter ranged from 10 to 20 μm. Large open pores originatingfrom large pores had a larger diameter than the large open poresincluded in the article with the foamed surface of Working Example 5,and the diameter ranged from 50 to 180 μm.

As shown in FIG. 11(b), small open pores originating from small poreshad a diameter ranging from 0.3 to 4 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 0.8 μm, and the latter was 97 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 67%.

Working Example 9

An article with a foamed surface was obtained with the same method as inWorking Example 6, except that an aqueous solution of sulfuric acid witha concentration of 86% was used in place of the 63% aqueous solution ofsulfuric acid.

The surface of the prepared article was observed with a scanningelectron microscope. An image obtained at 100 magnifications is shown inFIG. 12(a), and an image at 3000 magnifications in FIG. 12(b). As shownin FIG. 12(a), many open pores and many passages formed in the innerwalls of the open pores were observed in the surface of the surfacefoamed article, in the same manner as with the article with the foamedsurface obtained in Working Example 5. Large-diameter passages, formedby the connection of a large open pore with large pores, had a markedlylarger diameter than the equivalents in the article obtained in WorkingExample 8 had: The diameter ranged from 20 to 40 μm. The number oflarge-diameter passages was less than that of the equivalents in WorkingExample 8. Large open pores originating from large pores had a diameterwhich was essentially the same as the diameter of the large open poresincluded in the article with the foamed surface of Working Example 8,and the diameter ranged from 60 to 170 μm.

As shown in FIG. 12(b), small open pores originating from small poreshad a diameter ranging from 0.5 to 1 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 0.6 μm, and the latter was 92 μm.

A vertical section of the prepared article was observed through amicroscope at 500 magnifications. An obtained image is shown in FIG. 13.Large pores with a diameter from 30 to 50 μm were observed in the entiresuperficial layer with a thickness of about 120 μm, extending inwardsfrom the surface of a test piece of the superficial layer.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 65%.

Working Example 10

An article with a foamed surface was obtained with the same method as inWorking Example 7, except that an aqueous solution of sulfuric acid witha concentration of 86% was used in place of the 63% aqueous solution ofsulfuric acid.

The surface of the prepared article was observed with a scanningelectron microscope. An image obtained at 100 magnifications is shown inFIG. 14(a), and an image at 3000 magnifications in FIG. 14(b). As shownin FIG. 14(a), many open pores and many passages formed in the innerwalls of the open pores were observed in the surface of the surfacefoamed article, in the same manner as with the article obtained inWorking Example 5. Large-diameter passages, formed by the connection ofa large open pore with large pores, had a diameter which was essentiallythe same as the diameter of the large-diameter passages in the articleobtained in Working Example 9. The diameter ranged from 20 to 40 μm.Large open pores originating from large pores had a smaller diameterthan the equivalents in the article obtained in Working Example 9 had,and the diameter ranged from 30 to 80 μm.

As shown in FIG. 14(b), small open pores originating from small poreshad a diameter ranging from 0.2 to 1 μm.

The average diameter of the small open pores and that of the large openpores were calculated with the same method as in Working Example 1: Theformer was 0.6 μm, and the latter was 42 μm.

The proportion of the area of the large open pores to that of the entirephotograph was calculated with the same method as in Working Example 1,and it was 54%.

Preparation and Evaluation of Implant with Bioactive Substance WorkingExample 11

The article with the foamed surface prepared in Working Example 1 wasimmersed in an aqueous solution of calcium chloride with a calcium-ionconcentration of 2 M for 60 minutes, and subsequently in an aqueoussolution of dipotassium hydrogen phosphate with a phosphate-ionconcentration of 2 M for 60 minutes. A solution-immersed base was thusobtained.

Then the solution-immerse base was further immersed in pure water forthree hours, which was followed by washing of the base in pure water forten minutes while the pure water was being irradiated with ultrasound.Subsequently the washed base was dried at 120° C. for three hours. Animplant with a bioactive substance was obtained.

The surface of the implant was observed through a scanning electronmicroscope with 3000 magnifications. An image of the surface is shown inFIG. 15. On the surface and the inner walls of open pores formed in thesurface were observed particles adhering thereto, the particlesprecipitating from the aqueous solutions of calcium chloride anddipotassium hydrogen phosphate in which the article had been immersed.These particles were analyzed with an X-ray diffractometer. As a result,peaks belonging to hydroxyapatite were observed. These peaks were broad,which indicated that hydroxyapatite with low crystallinity was produced.

A photograph taken with a scanning electron microscope of the surface ofthe implant was made binary with an image processing software (“ScionImage” produced by Scion Corporation), or into portions with theparticles of hydroxyapatite and other portions. The proportion of thearea of the portions with hydroxyapatite particles on the surface of theimplant or the inner walls of open pores formed in the surface thereof,to the area of the entire photograph was calculated. The proportion was23%.

EXPLANATION OF REFERENCE NUMERALS 1 article with a foamed surface 2,202a, 202b body 3, 203a, 203b small pore 4, 204a, 204b large pores 5,205a, 205b superficial layer 6, 206a, 206b open pore 7, 207a, 207bpassage 8 isolated pore 9 connected pore 13, 213a, 213b small open pore14, 214a, 214b large open pore 15 small-diameter passage 16, 216a, 216blarge-diameter passage 210a, 210b bioactive substance 211a, 211b innerwall 212a, 212b implant A average diameter of the small pores B averagediameter of the large pores C diameter of the small-diameter passage Ddiameter of the large-diameter passage

We claim:
 1. A method of producing an article with a foamed surfacecomprising: a step 1 of forming small pores in a surface of a base madeof a plastic to produce a base with small pores; a step 2 of immersingthe base with small pores, obtained in step 1, in a solution including afoaming agent to prepare a foaming agent-including base; a step 3 ofimmersing the foaming agent-including base, obtained in step 2, in afoaming solution that makes the plastic swell and the foaming agent foamto prepare a foamed base; and a step 4 of immersing the foamed base,obtained in step 3, in a coagulating solution that coagulates theswollen plastic.
 2. The method as according to claim 1, furthercomprising applying the article with the foamed surface to an implant.3. The method according to claim 1, wherein the plastic is anengineering plastic.
 4. The method according to claim 1, wherein theplastic is polyetheretherketone.
 5. The method according to claim 1,wherein the plastic includes at least one fiber selected from the groupconsisting of carbon fiber, glass fiber, ceramic fiber, metal fiber andorganic fiber.
 6. The method according to claim 1, wherein the foamingsolution used in step 3 is concentrated sulfuric acid.
 7. The methodaccording to claim 1, wherein a porous structure formed in a superficiallayer of the foamed article is controlled by changing at least one of akind of the coagulating solution, a concentration of the coagulatingsolution and a time period for which the foamed base is immersed in thecoagulating solution.
 8. The method according to claim 1, wherein thecoagulating solution is at least one selected from the group consistingof water and a slow coagulating solution which takes a longer time tocoagulate the swollen plastic than water.
 9. The method according toclaim 8, wherein the slow coagulating solution is a solution of sulfuricacid with a concentration of less than 90%.
 10. The method according toclaim 1, wherein the foaming agent is a carbonate.
 11. The methodaccording to claim 10, wherein the carbonate includes at least onecarbonate compound selected from the group consisting of sodium hydrogencarbonate, sodium carbonate and potassium carbonate.
 12. A method ofproducing an implant comprising immersing an article with a foamedsurface, prepared by the method according to claim 1, both in a firstsolution including calcium ions and a second solution includingphosphate ions wherein the article may be first immersed in either ofthe first and second solutions.